DESCRIPTION (Adapted from applicant's description): Preterm, premature rupture of fetal membranes (PPROM) is a major pregnancy complication associated with significant perinatal morbidity and mortality and is considered a syndrome of multifactorial origin. The primary consequence of PPROM is preterm delivery. Intrauterine or systemic infection is considered an important cause of PPROM. In addition, preterm birth associated with PPROM can occur without any indication of either infection or maternal or fetal stress and it remains a frequent diagnosis in the Department of Perinatology at UCSD Medical Center. One of the reasons effective and safe methods for the prevention and treatment of PPROM are still not available is the fact that the actual mechanisms responsible for the initiation of PPROM are unclear. The present application proposes to elucidate a novel autocrine/paracrine mechanism underlying the role of Vascular Endothelial Growth Factor (VEGF) in fetal membrane rupture. As reported in our preliminary data, gene expression of VEGF in maternal decidua was elevated in patients with PPROM compared to those with preterm labor. Additionally, increased levels of VEGF receptor (Flt-1) mRNA was found at the rupture site of maternal decidua compared to the placental site, regardless of delivery etiology. The hypothesis to be tested is that excessive production of VEGF/Flt-1 leads to the activation of matrix metalloproteinases (MMPs), therefore enhancing collagen breakdown in human fetal membranes. The objective of the proposed study is to demonstrate a direct effect of VEGF on gene expression and activation of MMPs in cultured fetal membrane explants and to study cellular mechanisms of this interaction. Aim 1: To demonstrate that VEGF treatment of fetal membrane explants significantly enhances production of (MMP-1), -2,-3, and -9 in these tissues. Aim 2: To determine whether tissue plasminogen activator (tPA) is a key regulator of VEGF induced expression of MMPs. Aim 3: To elucidate the mechanism(s) of enhanced Flt-1 production in PPROM patients. The proposed studies will generate valuable information to consider new therapeutic management of PPROM patients, thereby improving perinatal outcome.